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Forkhead evolution and the FOXC1 inhibitory domain Open Access


Other title
anterior segment dysgenesis
transcription factor
Type of item
Degree grantor
University of Alberta
Author or creator
Fetterman, Christina
Supervisor and department
Walter, Michael (Medical Genetics)
Examining committee member and department
Sauve, Yves (Physiology)
Clark, Abbot (Cell Biology and Anatomy, University of North Texas)
Gallin, Warren (Biological Sciences)
Hughes, Sarah (Medical Genetics)
Medical Sciences - Medical Genetics

Date accepted
Graduation date
Doctor of Philosophy
Degree level
Forkhead (Fox) proteins are transcription factors that function in many processes including development, metabolism and cell cycle regulation. This gene family is divided into subfamilies that appear to originate from a common ancestor. I have identified the evolutionary selection pressures acting on individual amino acid positions in the FoxA, FoxC, FoxD, FoxI, FoxO and FoxP subfamilies. The patterns of selection observed allowed for the prediction of residue function and identification of residues that differentiate orthologs and paralogs. The subfamily structure and negative selection found within the subfamilies indicates that after gene duplication, differentiation of subfamilies through amino acid changes and subsequent negative selection on these changes has occurred. Meanwhile, the observed neutral changes and positive selection allow for further protein differentiation. Within the FoxC subfamily, positive selection was identified at one amino acid site in the inhibitory domain. Mutation of this site in FOXC1 alters transactivation activity and the effects of mutants on transactivation activity are different on different reporters. The mutant effects were consistent with those of known disease causing mutations, supporting the predicted positive selection. The inhibitory domain is known to function in reducing FOXC1 transactivation activity and influences protein stability. Here I additionally show that loss of the inhibitory domain and mutation of the positively selected site can reduce FOXC1 DNA binding. Co-transfection of FOXC1 and TLE4, a repressor protein that can potentially bind to the inhibitory domain, was shown to increase FOXC1 transactivation activity. The effects of a novel disease causing FOXC1 inhibitory domain mutation on FOXC1 function were also assessed. The mutation reduced FOXC1 transactivation activity and increased protein half-life both of which may lead to disease. Regulation of FOXC1 activity is critical for normal function and this work has furthered our knowledge of how the inhibitory domain influences FOXC1 activity. I have provided biological evidence for the theory that positive selection acts at the amino acid level to optimize protein function. I have also shown that both changes in transcription factor proteins and the cis-regulatory region of target genes have the potential to contribute to evolutionary adaptation.
License granted by Christina Fetterman ( on 2011-01-25T23:58:36Z (GMT): Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of the above terms. The author reserves all other publication and other rights in association with the copyright in the thesis, and except as herein provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
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File title: Forkhead Evolution and the FOXC1 Inhibitory Domain
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